Description:

Despite multiple attempts, no pharmacological agent thus far has been successful in increasing high-density lipoprotein (HDL) while reducing coronary events. Dalcetrapib is a cholesteryl-ester-transfer protein (CETP) inhibitor that has not shown off-target effects such as blood pressure elevation (noted with torcetrapib, another CETP inhibitor in the ILLUSTRATE trial) in early trials. The current trial was a phase III trial designed to assess the efficacy and safety of dalcetrapib on clinical outcomes in patients with recent acute coronary syndrome (ACS) who were already on background evidence-based therapy.

Hypothesis:

Dalcetrapib would be superior to placebo in reducing cardiovascular events in patients with recent ACS who were already on background evidence-based therapy.

Concomitant Medications:

Principal Findings:

This was an event-driven trial, which was terminated early due to futility. At this time, a total of 15,871 patients were randomized at 935 sites in 27 countries, 7,933 to dalcetrapib and 7,938 to placebo. About 24% had diabetes mellitus, 68% had hypertension, and 63% met criteria for the metabolic syndrome. About 85% of patients presented with biomarker-positive ACS, with a mean time from index hospitalization to randomization of 61 days. Revascularization was undertaken in 91% of patients. The mean baseline low-density lipoprotein (LDL) and HDL cholesterol values were 76 and 42 mg/dl, respectively. Median baseline high-sensitivity C-reactive protein (hs-CRP) was 1.5 mg/L.

Interpretation:

The results of the large phase III dal-OUTCOMES trial indicate that raising HDL with dalcetrapib in patients with a recent ACS was not superior to placebo in improving cardiovascular (CV) outcomes in patients who were already on evidence-based secondary prevention measures. These results are similar to the negative results noted with torcetrapib (also a CETP inhibitor) in the ILLUMINATE trial and niacin in the AIM-HIGH trial (both in stable outpatients). Trials with dalcetrapib (in stable patients with coronary artery disease), and other HDL-raising agents such as anacetrapib (another CETP inhibitor), are ongoing. However, results of the other dalcetrapib trial will likely be moot since Roche recently discontinued further development of dalcetrapib. One of the biggest conundrums in cardiology is that although low HDL is associated with a higher risk of adverse CV outcomes, no pharmacological agent to date that raises HDL has demonstrated clinical efficacy in large outcomes trials. It remains to be investigated if other aspects such as HDL size and density are more important than absolute HDL levels in improving CV outcomes.

Similar to torcetrapib, dalcetrapib was also associated with off-target effects such as raised systolic blood pressure and elevated hs-CRP. This raises the possibility of a class effect for this off-target effect with CETP inhibitors. Further research is necessary to elucidate the mechanisms behind this effect.

References:

Presented by Dr. Gregory Schwartz at at the American Heart Association Scientific Sessions, Los Angeles, CA, November 5, 2012.